The binding of sigma factors to core RNA polymerase is essential for specific initiation of transcription in eubacteria and is thus critical for cell growth. Since the responsible protein-binding regions are highly conserved among all eubacteria but differ significantly from eukaryotic RNA polymerases, it is a promising target for drug discovery. A homogeneous assay for sigma-binding to RNA polymerase (E. coli) based on luminescence resonance energy transfer (LRET) has been developed in our lab using an europium-labeled sigma70 and IC5-labeled fragment of the beta-prime subunit of RNA polymerase (amino acid residues 100-309). Inhibition of sigma binding was measured by the loss of LRET through a decrease in IC5-emission.The technical advances offered by LRET resulted in a very robust assay suitable for a high-throughput screening and was successfully used to screen a crude natural product library. We would like to refine this assay, to develop appropriate counter-screens to minimize the number of false positives, and to develop further methods for characterizing the confirmed hits. Then we will use these assays to screen much larger libraries and hopefully to identify and characterize chemical compounds that might represent lead compounds for new antibiotic drug development. [unreadable] [unreadable]